Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
  • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
  • A61K41/10—Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person
  • A61K41/17—Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person by ultraviolet [UV] or infrared [IR] light, X-rays or gamma rays
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
  • A61L2/02—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using physical processes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
  • A61L2/02—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using physical processes
  • A61L2/08—Radiation
  • A61L2/084—Visible light
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
  • A61L2/02—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using physical processes
  • A61L2/08—Radiation
  • A61L2/088—Radiation using photocatalysts or photosensitisers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
  • A61L2/02—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using physical processes
  • A61L2/08—Radiation
  • A61L2/10—Ultraviolet [UV] radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
  • A61L2/16—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using chemical substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N5/00—Radiation therapy
  • A61N5/06—Radiation therapy using light
  • A61N5/0613—Apparatus adapted for a specific treatment
  • A61N5/062—Photodynamic therapy, i.e. excitation of an agent
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2103/00—Materials or objects being the target of disinfection or sterilisation
  • A61L2103/05—Living organisms or biological materials

Definitions

• the invention relates to a preparation for photodynamic control of microorganisms in accordance with the features listed in patent claim 1 .
• the invention furthermore relates to the use of such a preparation.
• WO 01/87416 A1 is an arrangement and method for reducing or destroying microorganisms such as bacteria using a light-activatable substance, known from photodynamic therapy (PDT).
• a light-activatable substance known from photodynamic therapy (PDT).
• the microorganisms are sensitized and/or stained, and, after irradiation with light having a suitable wavelength and energy density, are killed.
• the principle of action of PDT is based on the physical action of the transfer of energy to the light-activatable substance, which is also called the photosensitizer. From there, the energy for reactions can be made available to the cell membrane.
• the energy produced by means of an irradiation device in particular a laser device, is thus concentrated on the microorganisms and the equilibrium of reactions that also occur in the non-irradiated condition in the “normal” environment are [sic] displaced and consequently the microorganisms are destroyed.
• EP 0 637 976 B1 is the use of a light-sensitizing substance or compound or photosensitizer (PS) in the production of a medication for use during disinfection or sterilization of tissue in the oral cavity or of a wound or lesion in the oral cavity by destroying microbes that are associated with a disease and that are in a periodontal pocket in the region between the tooth and the gum.
• the photosensitizer is applied to the tissue, wound, or lesion, the microbes associated with a disease absorbing the photosensitizer.
• the tissue, wound, or lesion is irradiated with laser light at a wavelength that the photosensitizer absorbs.
• microbes and photosensitizers in the form of solutions that include, among other things, methylene blue and toluidine blue in different, quite small concentrations, specifically from 0.01 to 0.00125% (weight per volume), the effect of the applied energy density also being covered.
• HeNe lasers with a wavelength of 634 nm and an output of 7.3 mW as well as GaAs lasers with a wavelength of 660 nm and an output of 11 mW are used for light sources.
• Photodynamic therapy is a photochemical method that in the past was used primarily in cancer treatment.
• the term “photodynamic therapy” in general is understood to be light-induced inactivation of cells, microorganisms, and molecules.
• APT antimicrobial photodynamic therapy
• the goal is not to destroy endogenous (tumor) cells, but rather the deliberate control of local infections, the control of microorganisms.
• the principle of action of APT is based on the selective staining of microorganisms in the biofilm using a so-called photosensitizer and the destruction of the microorganisms using irradiation with a suitable laser matched to the photosensitizer.
• Substances that can be used for photosensitizers are able to absorb light of a suitable wavelength and thereby convert to the excited so-called triplet state.
• Systemically applicable photosensitizers are used primarily in cancer therapies. These are directed against endogenous cells, are administered systemically according to certain pharmacological principles in order to enrich tumors with them and then to activate them using irradiation with light. This application is distinguished in principle from that for controlling superficial infections.
• the active substance should:
• Photosensitizers can absorb light (energy) into their structure and them make it available again for further reactions as chemical energy. A special excited and very reactive form of oxygen is then formed from the oxygen molecules that are present in the environment of the excited photosensitizer molecules—so-called singlet oxygen.
• the photosensitizing substances react according to given reaction paths.
• the photons h radiated in during the antimicrobial photodynamic therapy excite the photosensitizer coupled to the microorganisms ( 1 Sens) due to its high absorbability (Equation 1).
• the excited sensitizer molecule converts to a metastable triplet condition with a longer lifetime, in accordance with Equation (2).
• the time in the triplet condition (in the range of microseconds) is relatively long compared to other excitation conditions (in the picosecond and nanosecond range) and therefore is ideal as a starting point for photochemical reactions such as e.g. transferring the excitation energy to an oxygen molecule.
• the excited oxygen assumes the energetically higher singlet condition with a relatively longer lifetime (Equation 3).
• the basic principle of the antimicrobial photodynamic effect is thus based on the local formation of singlet oxygen and consequently of reactive radicals.
• This activated singlet oxygen initiates oxidation of molecules primarily in the cell wall of the microorganisms and thus initiates cytolysis.
• the photosensitizer is not consumed with the energy doses applied if these are in the range of 3 J/cm2 to 6 J/cm2, because in this so-called photobleaching—the destruction of the photosensitizer molecule by light—cannot be detected but rather remains in or on the tissue.
• photobleaching the destruction of the photosensitizer molecule by light—cannot be detected but rather remains in or on the tissue.
• treated areas exposed to sunlight can continue to react in an undesired manner and cause secondary effects.
• the underlying object of the invention is to further develop the preparation such that improved control of microorganisms is attained.
• photosensitizers such as for instance phenothiazine dyes, without this being a limitation, can react in various structurally similar forms depending on the nanoenvironment, as can be seen in the following for methylene blue:
• the leucoform of the methylene blue is for instance not photoactive and is colorless, while the o- and p-chinoid forms are suitable photosensitizers.
• Glutathione in reduced (GSH) and oxidized (GSSG) forms have the following structures:
• Glutathione is an amino acid derivative that plays a different important role in the metabolism of cells and that is present in a high concentration. Glutathione is included in a redox cycle in that it occurs in oxidized form (GSSG) and in reduced form (GSH). Oxidized glutathione comprises two tripeptides chained to one another by a disulfide compound, while the reduced thiol form represents a single tripeptide with one free sulfhydryl group. In this redox system, the reduction of GSSG to GSH is catalyzed by the glutathione reductase. Equilibrium is sharply displaced in favor of the reduced glutathione and NADPH is required for cofactor.
• glutathione In animal cells, glutathione has numerous key positions in internal biochemical processes, the effect of antioxidants probably being very important. Moreover, it plays an enormous role in the metabolism of cysteine-containing proteins and is involved in the deactivation of toxic, electrophilic agents during enzyme transports catalyzed by sulfur compounds.
• GSH assumes the task of a sulfhydryl buffer that, among other things, is to obtain the cysteine group of hemoglobin and other erythrocyte proteins in their reduced form.
• glutathione redox cycle for retaining normal mitochondrial function, whereby the GSH level here correlates to the activity of the carnitine acylcarmitine translocase, which thereby becomes an indicator for glutathione presence in the cells.
• Glutathione possesses an important detoxification function during the production of by-products, such as hydrogen peroxides and natural peroxides, that is inevitable in aerobic life. Glutathione is involved in a specific scavenger system of the cells that is meant to counteract the oxygen radicals that provoke numerous changes.
• hydrogen peroxide and lipid peroxide are metabolized in the glutathione cycle in a reaction, catalyzed by glutathione peroxidase, with reduced glutathione while forming water and oxygen, which occurs in a large number of cells.
• the oxidized dimer of glutathione (GSSG) thus formed is then subsequently reduced to GSH again in the subsequent redox cycle.
• Mitochondrial or glycolytic paths can lead to inhibition of ATP synthesis due to peroxide that has not been detoxified.
• the glutathione as protector recedes to a designed protective mechanism for the cell, which mechanism, with the use of glutathione and other reduction equivalents, prevents peroxide formations from occurring (on fatty acid chains).
• the myocytes are also naturally equipped with such an antioxidative enzyme system that contains superoxide dismutase (SOD) and catalase in addition to the glutathione redox system in order to protect itself from damage due to reactive compounds.
• SOD superoxide dismutase
• catalase in addition to the glutathione redox system in order to protect itself from damage due to reactive compounds.
• Glycine should also be mentioned; it forms in the glutathione-exhausted heart, presumably after the breakdown of reduced myocytes. Glycine's involvement in the detoxification of acyl CoA, an amphipathic molecule with limiting surface active properties and that accumulates particularly during myocardial ischemia, is not insignificant. Thus, in addition to the “switching function” of glutathione with respect to the inventive protonation of the photosensitizer, there is also a protective effect against damage due to the effect of the singlet oxygen on the local tissue.
• Ascorbic acid possesses the following structures:
• ascorbic acid is a six-member carbon ketol actone related to glucose and other hexoses and is a water-soluble vitamin. In the body, it is reversibly oxidized to dehydroascorbic acid; it thus acts in the framework of a redox equilibrium as an electron donor and electron acceptor, which is also the basis for its main biological action.
• the significant redox processes occur between L-ascorbic acid (acts as 1-electron donor) and the radical L-semihydroascorbic acid.
• radical scavenger proceeds from specific scavenger systems with which the cells are equipped in order to protect themselves from oxygen radicals and other toxic oxygen metabolites that very clearly can lead to reversible and irreversible tissue damage, including damage to the myocardium.
• the free radicals can cause different types of damage, whereby peroxidation of membrane phospholipids and oxidation of sulfhydryl compounds are certainly the most significant.
• Ascorbic acid is among the most highly reducing agents in the biological milieu.
• the photodynamic effect can be controlled using protonation of the photosensitizer and control of the radical chain reaction.
• Quinones act with redox reactions in mitochondria (respiratory chain) and chloroplasts (photosythesis). A differentiation is made between ubiquinones and plastoquinones, which are characterized by different side chain groups on the quinone ring. As “coenzyme Q”, an ubiquinone assumes a key position as primary electron acceptor in the photosystem II of the photosynthesis.
• Single or multivalent alcohols that are dehydrated to aldehydes can also act as proton donors.
• Protonation and deprotonation of the photosensitizer can also be intensified and controlled using suitable enzymes such as for instance using xanthin dehydrogenase.
• Xanthin dehydrogenase is an enzyme with relatively low substrate specificity. It transfers hydrogen e.g. from formaldehyde or acetaldehyde to a suitable acceptor. This is possible for instance with the aforesaid methylene blue.
• the enzyme xanthin dehydrogenase can also be inhibited using urethane.
• a similar reaction can be attained using the succinate dehydrogenase enzyme system, which catalyzes the succinate>fumarate step—a reaction that occurs in the citrate cycle. It can be competitively inhibited using a number of substances that are similar to the succinate.
• NAD nicotinamide adenine dinucleotide
• One of the protons is bonded by NAD+ directly to the nicotinamide ring; the other remains in solution.
• NAD+ is a coenzyme—it never acts alone, but rather only after bonding to a protein.
• NAD+-bonding proteins belong to the dehydrogenase class. All of them catalyze the same chemical reaction (see above), but they are different from one another in terms of their substrate specificity. Thus among many others there are alcohol dehydrogenase, lactate dehydrogenase, malate dehydrogenase, glycerin aldehydphosphate dehydrogenase, etc.
• the singlet oxygen that occurs during irradiation is also rapidly eliminated by the hydrogen atoms that are present in water.
• the chemically equivalent isotope deuterium is very rare.
• this elimination is significantly reduced and thus the antibacterial effect is intensified because the nanoenvironment of the bonded excited photosensitizer molecules and the singlet oxygen released by them is a deuterium environment rather than a hydrogen environment.
• a longer lifetime for the singlet oxygen means more reactivity against bacteria membrane molecules. This can be attained by replacing hydrogen with deuterium in the range of 0 to 100%.
• One special embodiment of the invention is a rinse solution with which photodynamic control is further optimized.
• the actions are described for both the preparation described in the foregoing and for the rinse solution.
• Dyes for histological staining are composed of two essential components:
• Chromophore group (dye carrier),
• a chromophore group does not make a chemical into a dye, although it can appear colored to the eye.
• auxochrome color aid
• auxochrome determines the classification as acid or basic dye. They are generally present in the form of the associated salts.
• Dye solutions comprise dissolved dye molecules that react more or less specifically to membranes. Bacteria can be stained with methylene blue and detected in so-called simple staining.
• the cellular membranes of microorganisms and cells are highly specific structures. Interaction with the environment is determined by local concentrations and charge conditions. Contact with the membrane is required for a molecule, for instance of a dye, to react.
• This staining of bacteria occurs in aqueous solutions of 0.1% to 1% and as a rule these have a pH of 3-4.
• the staining molecule portion, the dye cation is deposited on the wall of the bacteria using its positive surface charge, whereby these dyes are also called vital dyes.
• the dye reaction also depends in part on the pH of the specimen to be stained.
• An acid pH intensifies the reaction with the basic methylene blue (blue dye).
• the accumulated dye cation is now used as a “photochemical machine” that absorbs the laser light and is converted to chemical energy, which is used for the production of singlet oxygen.
• the irradiation is influenced primarily by the selection of a suitable wavelength, which should approach the absorption maximum for the dye, and the selection of adequate surface and energy densities, but primarily also by the uniform spatial distribution of the light. This is especially critical when complex structures with different optical properties have to be treated, such as teeth, bones, and mucosa in a single area.
• the therapy area is prepared, after the staining and prior to the irradiation, by rinsing out the dye solution with a suitable rinse solution.
• the pockets were irradiated with a laser via optics and then all of the pockets were rinsed thoroughly with an aqueous solution in order to remove as much residual dye as possible.
• Patient 1 Patient 1 Patient 1 Patient 2 Patient 2 Patient 2 Prior to After After Prior to After After Type of bacteria treatment irradiation 1 irradiation 2 treatment irradiation 1 irradiation 2 Actinobacillus actinomycetemcom.
• the effect of the light can be improved with deliberate adjustment of optical and chemical parameters and the most undisturbed sequence for the photochemical reaction chain can be assured.
• the rinse solution should possessed [sic] at least one of the following properties:
• the mean free path length for the reactive singlet oxygen molecules is approx. 0.2 nm. Therefore their reaction options are also limited to this radius around the molecule.
• the dye molecules remaining in free solution are thus not useful in the sense of the therapy, but rather even impede the therapeutic effect by increasing the extinction.
• rinse solutions with an aqueous or non-aqueous basis that have at least one of the following properties:
• the preparation that contains dye or is a dye is initially applied in a high concentration to the area to undergo therapy and then rinsing is performed with the rinse solution, in particular water and/or with a basic pH that is as high as possible. Then the irradiation is performed by means of the light from the irradiation device, optimized cell damage occurring in a preferred manner. It has proved particularly effective to initially apply the preparation in a high concentration to the area to undergo therapy and then to rinse with the rinse solution, in particular water and/or with an oxygen partial pressure that is as high as possible, and finally to perform the irradiation by means of the light from the aforesaid light source, optimized cell damage preferably occurring.
• the light-activatable substance is begun slowly and is applied by means of syringe so that it covers the surface of the infected tissue area.
• the quantity must be selected such that the surfaces of the infected areas are wetted with the thinnest possible coating of the light-activatable substance. It should be ensured that the niches and pockets in the tissue are completely wetted. Likewise, the air blower should be used if there is complex morphology.
• the exposure time for the light-activatable substance is at least 60 sec. After rinsing for at least 3 sec with simultaneous suctioning of excess solution (deposits of dye must be removed!), irradiate with the irradiation device.
• the correct dosage of energy, the irradiation is significant in terms of the bacteria-reducing effect and is thus significant for the treatment results.
• PS photosensitizer
• a daily maximum dosage up to 200 mg is provided for the 1% solution for injection used as antidote. This means a kg dosage per day of approx. 3 mg for an adult and 10 mg/day/kg for a child.
• Another significant factor that relates to rinsing out the preparation or the photosensitizer (PS) prior to irradiation is the high absorption of the preparation or the photosensitizer (PS) in the range of the wavelength of the light applied.
• the pH value for the rinse solution is preferably more basic. It preferably has a pH of 7 to 9.
• the oxygen partial pressure is preferably high.
• the rinse solution in particular prepared tap water, has oxygen partial pressure in the range of 4 to 6 mg/l for rinsing.
• the rinse solution is usefully enriched with molecular oxygen up to 14 mg/l.
• peroxide enrichment has proved useful, specifically preferably as 0.5% to 3% hydrogen peroxide solution.

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• 2005
  • 2005-04-15 DK DK05731056.7T patent/DK1737492T3/da active
  • 2005-04-15 KR KR1020067021339A patent/KR101226665B1/ko not_active Expired - Fee Related
  • 2005-04-15 EP EP05731056.7A patent/EP1737492B9/de not_active Expired - Lifetime
  • 2005-04-15 SI SI200531677T patent/SI1737492T1/sl unknown
  • 2005-04-15 ES ES05731056T patent/ES2401148T3/es not_active Expired - Lifetime
  • 2005-04-15 PL PL05731056T patent/PL1737492T3/pl unknown
• 2010
  • 2010-07-20 US US12/839,846 patent/US9034622B2/en not_active Expired - Lifetime
• 2011
  • 2011-10-28 JP JP2011237411A patent/JP5586561B2/ja not_active Expired - Fee Related
• 2014
  • 2014-06-09 JP JP2014118870A patent/JP2014208667A/ja active Pending

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